Combination of ruthenium (II) polypyridyl complex Δ-Ru1 and Taxol enhances the anti-cancer effect on Taxol-resistant cancer cells through Caspase-1/GSDMD-mediated pyroptosis

• Published in: Journal of inorganic biochemistry 2022-05, Vol.230, p.111749-111749, Article 111749
• Main Authors: Chen, Dan, Guo, Shunwen, Tang, Xingguo, Rong, Yi, Bo, Huaben, Shen, Han, Zhao, Zizhuo, Qiao, Aimin, Shen, Juan, Wang, Jinquan
• Format: Article
• Language: English
• Subjects: Animals; Caspase 1 - metabolism; Combination therapy; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Mice; Neoplasms; Paclitaxel - pharmacology; Phosphate-Binding Proteins - metabolism; Pore Forming Cytotoxic Proteins; Pyroptosis; Ruthenium - chemistry; Ruthenium complex; Synergistic effect; Taxol
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2022.111749

Taxol is the first-line drug for cancer treatment. However, tumor resistance to Taxol is still a significant challenge in clinical practice. Here, we studied the synergistic effect of a ruthenium (II) polypyridyl complex, Δ-[Ru(bpy)2(HPIP)](ClO4)2(Δ-Ru1, where bpy = 2,2′-bipyridine, HPIP = 2-(2-hydroxyphenyl) imidazo[4,5-f] [1, 10] phenanthroline) combined with Taxol (Δ-Ru1 & Taxol) on Taxol resistant cervical cancer HeLa cell line (HeLa/Taxol). The results of the Chou-Talalay and Synergyfinder analytical test show that the Δ-Ru1 & Taxol combination has a synergistic effect in HeLa/Taxol cells. Especially, vesicles structures were observed on the membranes of HeLa/Taxol cells treated with Δ-Ru1 & Taxol, accompanied by cell swelling, which characterizes pyroptosis. Furthermore, the release of Interleukin-1β (IL-1β) and Lactate Dehydrogenase (LDH) were increased. At the same time, the activation and cleavage of Caspase-1 and Gasdermin D (GSDMD), the key molecules of the pyroptosis pathway, were detected. In addition, the Δ-Ru1 & Taxol combination had a synergistic anti-tumor effect in the mice model and could effectively inhibit tumor growth and significantly reduce the side effects on the lungs and the neuroethology of Taxol. Taken together, the Δ-Ru1 & Taxol combination can induce cell death through Caspase-1/GSDMD-mediated pyroptosis to enhance the therapeutic effect on HeLa/Taxol cells. This study provides a novel idea for the combined application of ruthenium complexes and other drugs, which may be utilized to overcome cancer drug resistance. Ruthenium (II) polypyridyl complex Δ-Ru1 and Taxol enhances the therapeutic effect on Taxol-resistant cancer cells. The Δ-Ru1 & Taxol combination inhibits cell proliferation and induces pyroptosis by increasing cellular reactive oxygen species (ROS) accumulation and activating the Caspase-1/ Gasdermin D signaling pathway. [Display omitted] •l  Ru (II) polypyridyl complex, Δ-Ru1, has high-efficiency/low-toxicity in anti-cancer therapy.•l  Δ-Ru1 may be used in combination with clinical chemotherapeutic drugs to anti-cancer.•l   Δ-Ru1 and Taxol enhances the therapeutic effect on Taxol-resistant cancer cells.•l  Δ-Ru1 and Taxol combination activates Caspase-1/Gasdermin D-mediated pyroptosis.•Δ-Ru1 and Taxol combination had a synergistic anti-tumor effect in the mice model.